Skip to main content
eScholarship
Open Access Publications from the University of California

Regulation of S100A8 Stability by RNF5 in Intestinal Epithelial Cells Determines Intestinal Inflammation and Severity of Colitis.

  • Author(s): Fujita, Yu
  • Khateb, Ali
  • Li, Yan
  • Tinoco, Roberto
  • Zhang, Tongwu
  • Bar-Yoseph, Haggai
  • Tam, Miguel A
  • Chowers, Yehuda
  • Sabo, Edmond
  • Gerassy-Vainberg, Shiran
  • Starosvetsky, Elina
  • James, Brian
  • Brown, Kevin
  • Shen-Orr, Shai S
  • Bradley, Linda M
  • Tessier, Philippe A
  • Ronai, Ze'ev A
  • et al.
Abstract

Inflammatory bowel disease (IBD) is prevalent, but the mechanisms underlying disease development remain elusive. We identify a role for the E3 ubiquitin ligase RNF5 in IBD. Intestinal epithelial cells (IECs) express a high level of RNF5, while the colon of Rnf5-/- mice exhibits activated dendritic cells and intrinsic inflammation. Rnf5-/- mice exhibit severe acute colitis following dextran sodium sulfate (DSS) treatment. S100A8 is identified as an RNF5 substrate, resulting in S100A8 ubiquitination and proteasomal-dependent degradation that is attenuated upon inflammatory stimuli. Loss of RNF5 from IECs leads to enhanced S100A8 secretion, which induces mucosal CD4+ T cells, resulting in Th1 pro-inflammatory responses. Administration of S100A8-neutralizing antibodies to DSS-treated Rnf5-/- mice attenuates acute colitis development and increases survival. An inverse correlation between RNF5 and S100A8 protein expression in IECs of IBD patients coincides with disease severity. Collectively, RNF5-mediated regulation of S100A8 stability in IECs is required for the maintenance of intestinal homeostasis.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
Current View